JAMA Neurology publishes Phase 3 study results on the efficacy and safety of FINTEPLA®▼(fenfluramine) oral solution for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS)
- Primary endpoint was met demonstrating that fenfluramine, as adjunctive treatment, is effective in significantly reducing the frequency of drop seizures in LGS patients compared to placebo1
- LGS is a severe childhood-onset developmental and epileptic encephalopathy characterized by drug-resistant seizures with high morbidity2
- Fenfluramine was recently approved by the U.S. Food and Drug Administration (FDA), as a treatment option for the treatment of seizures associated with LGS, a rare and devastating lifelong childhood-onset epilepsy5
UCB, a global biopharmaceutical company, announced on May 2, 2022 the publication in JAMA Neurology of its multi-centre, double-blind, placebo-controlled, parallel-group, randomised Phase 3 trial demonstrating that fenfluramine 0.7 mg/kg/day, when added to a patient’s current anti-epileptic treatment regimen for seizures associated with LGS, is effective in reducing the frequency of drop seizures.1 Drop seizures cause a person to suddenly lose muscle tone, become limp, and fall to the ground, with a high likelihood of injury.6 Within the study, drop seizures were further defined as generalised tonic-clonic (GTC), secondary GTC [focal to bilateral tonic clonic], tonic, atonic, or tonic and atonic.1
LGS is a severe childhood-onset developmental and epileptic encephalopathy characterised by drug-resistant seizures with high morbidity2 as well as serious impairment of neurodevelopmental, cognitive and motor functions.3 LGS has far-reaching effects beyond seizures, including issues with communication, psychiatric symptoms, sleep, behavioral challenges and mobility.7
The trial met its primary efficacy endpoint. Patients taking fenfluramine 0.7 mg/kg/day experienced an estimated mean difference in the reduction of drop seizure frequency by 19.9% from placebo (P=.001). The median percent reduction in the frequency of drop seizures in the 0.7 mg/kg/day group was 26.5%, compared with 14.2% in the 0.2mg/kg/day group, and 7.6% in patients taking placebo (P=.09). In key secondary outcomes, the trial demonstrated that a greater proportion of patients taking fenfluramine experienced a 50% or greater reduction in drop seizure frequency, compared to patients in the placebo group.1
“Our trial data and the clinical evidence demonstrate the safety and efficacy of fenfluramine for the treatment of seizures associated with LGS and especially for patients where generalised tonic-clonic seizures are the predominant seizure type, where there is a greater risk of mortality,” said Kelly Knupp, M.D., MSCS, FAES, Associate Professor, Children’s Hospital Colorado, Principal Investigator of the study. “LGS is a highly treatment-resistant developmental and epileptic encephalopathy and we need differentiated treatment options, such as fenfluramine, which has a unique mechanism of action different from and complementary to current seizure medications.”
The study also included seizure-type subgroup analyses that demonstrated that fenfluramine 0.7mg/kg/day was highly effective in reducing the frequency of GTCs in nearly 50% of patients. During the maintenance and titration period, patients experienced a decrease in frequency of 45.7% in the fenfluramine 0.7mg/kg/day group, a decrease in frequency of 58.2% in the 0.2 mg/kg/day fenfluramine group, compared with an increase in frequency of 3.7% in the placebo group (P=.001 and P<.001 respectively). The percentage reduction in tonic or atonic seizure frequency was 46.7% in the fenfluramine 0.7mg/kg/day group, compared with 6.8% in the placebo group (P=.046).1
The reason these data are compelling is because GTCs are commonly observed in patients with LGS.9 Moreover, GTCs may result in bodily injury.10,11 Sudden unexpected death in epilepsy (SUDEP) is a major concern for people living with LGS and patients with a history of GTCs have an estimated 10-fold greater risk of SUDEP.4
Fenfluramine was generally well-tolerated in this study. The most common treatment-emergent adverse events included decreased appetite (22%), somnolence (13%), and fatigue (13%).1 The fenfluramine safety database includes long-term cardiovascular safety data for patients treated for up to three years in DS and LGS.5
“This study further validates the importance of fenfluramine as a new treatment option for seizures associated with LGS, including generalised tonic-clonic seizures,” said Mike Davis, Global Head of Epilepsy, UCB. “Through our close connection with the LGS community, we know the challenges they face go beyond treatment resistant seizures to include difficulty with behavior and cognition, and we hope that fenfluramine can provide relief for people living with LGS.”
Site investigators and caregivers also rated patients as significantly much or very much improved on the Clinical Global Impression of Improvement (CGI-I) scale (investigators 26% vs. 20% vs. 6% and caregivers 34% vs. 27% vs. 5% for 0.7 mg/kg vs. 0.2 mg/kg vs. placebo, respectively).1
Fenfluramine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of LGS in patients aged 2 and older in March 2022.5 Fenfluramine was also approved for the treatment of Dravet Syndrome in patients aged 2 and older in June 20205 and by the EU Commission in December 2020 as an add-on treatment for seizures associated with Dravet syndrome in patients aged 2 and older.12 UCB acquired Zogenix, Inc. and FINTEPLA® on March 7, 2022.
- Knupp K, Scheffer, I, et al. Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated with Lennox-Gastaut Syndrome: A Randomized Clinical Study. JAMA Neurology. 2022; E1-E11.
- Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies. CNS Drugs. 2021;35(1):61-83.
- Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8(1):82-93.
- Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Clinical risk factors in SUDEP: A nationwide population-based case-control study. Neurology. 2020;94(4):e419-e429.
- FINTEPLA® (fenfluramine) oral solution CIV. U.S. Prescribing Information. March 2022. Available at : https://zogenix.com/pi/Fintepla-prescribing-information.pdf. Last accessed: April 2022
- Mastrangelo M. Lennox-Gastaut Syndrome: A State of the Art Review. Neuropediatrics. 2017;48(3):143-151.
- LGS Foundation. LGS Characteristics and Major Concerns Survey. https://www.lgsfoundation.org/wp-content/uploads/2021/08/2019-PFDD-Caregiver-Survey-1.pdf. Accessed April 2022.
- UCB Data on file. Zogenix, Inc. bioStrategies Group. 2021.
- Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert opinion on the management of Lennox-Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol. 2017;8:505.
- Gastaut H, Roger J, Soulayrol R, et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as “petit mal variant”) or Lennox syndrome. Epilepsia. 1966;7(2):139-179.
- Cross JH, Galer BS, Gil-Nagel A, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021;93:154-159.
- FINTEPLA Summary of Product Characteristics. September 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/fintepla-epar-product-information_en.pdf. Last accessed: April 2022
- Zogenix Press Release. Zogenix Submits New Drug Application for FINTEPLA® (Fenfluramine) in Japan for the Treatment of Epileptic Seizures Associated with Dravet Syndrome. 21 December 2021. Available at: https://www.globenewswire.com/news-release/2021/12/21/2356048/0/en/Zogenix-Submits-New-Drug-Application-for-FINTEPLA-Fenfluramine-in-Japan-for-the-Treatment-of-Epileptic-Seizures-Associated-with-Dravet-Syndrome.html#:~:text=21%2C%202021%20(GLOBE%20NEWSWIRE),fenfluramine)%20for%20the%20treatment%20of. Last accessed: April 2022
- Zogenix Press Release. Zogenix Submits Type II Variation Application to the European Medicines Agency (EMA) to Expand the Use of FINTEPLA® (fenfluramine) for the Treatment of Seizures Associated with Lennox-Gastaut Syndrome. 20 December 2021. Available at: https://zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-submits-type-ii-variation-application-european-medicines. Last accessed: April 2022.
Please see full Prescribing Information, including Boxed Warning, for additional important information on FINTEPLA.
Refer to the European Summary of Product Characteristics for other adverse reactions and full prescribing information. Date of revision: 04 Nov 2021.
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.